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Pyrrole–Aminopyrimidine Ensembles: Cycloaddition ofGuanidine to Acylethynylpyrroles

Olga V. Petrova, Arsalan B. Budaev, Elena F. Sagitova, Igor A. Ushakov, Lyubov N. Sobenina, Andrey V. Ivanovand Boris A. Trofimov *

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Citation: Petrova, O.V.; Budaev,

A.B.; Sagitova, E.F.; Ushakov, I.A.;

Sobenina, L.N.; Ivanov, A.V.;

Trofimov, B.A. Pyrrole–

Aminopyrimidine Ensembles:

Cycloaddition of Guanidine to

Acylethynylpyrroles. Molecules 2021,

26, 1692. https://doi.org/

10.3390/molecules26061692

Academic Editor: Jacek Nycz

Received: 26 February 2021

Accepted: 12 March 2021

Published: 17 March 2021

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4.0/).

A.E. Favorsky Irkutsk Institute of Chemistry, Siberian Branch, Russian Academy of Sciences, 1 Favorsky Street,664033 Irkutsk, Russia; ol_petr@irioch.irk.ru (O.V.P.); arsalan@irioch.irk.ru (A.B.B.); sagitova@irioch.irk.ru (E.F.S.);igor-papa71@mail.ru (I.A.U.); sobenina@irioch.irk.ru (L.N.S.); ivanov@irioch.irk.ru (A.V.I.)* Correspondence: boris_trofimov@irioch.irk.ru; Tel.: +7-(3952)-41-93-46

Abstract: An efficient method for the synthesis of pharmaceutically prospective pyrrole–aminopyrimidineensembles (in up to 91% yield) by the cyclocondensation of easily available acylethynylpyrroles withguanidine nitrate has been developed. The reaction proceeds under heating (110–115 ◦C, 4 h) in theKOH/DMSO system. In the case of 2-benzoylethynylpyrrole, the unexpected addition of the formedpyrrole–aminopyrimidine as N- (NH moiety of the pyrrole ring) and C- (CH of aminopyrimidine)nucleophiles to the triple bond is observed.

Keywords: acylethynylpyrroles; guanidine; cyclocondensation; aminopyrimidine

1. Introduction

One of the main trends in modern organic chemistry is the synthesis of heterocyclic en-sembles, each of the fragments of which has promising biological activity. These ensemblesinclude, in particular, pyrrole–pyrimidines, which combine two of the most fundamentallife-supporting molecular systems in their molecule and represent privileged objects fordrug design.

The pyrrole core is a key structural motif in a plethora of natural products suchas chlorophyll, hemoglobin, bile pigments, vitamin B12, and others [1]. Pyrrole and itsderivatives are also important components of a number of pharmaceuticals and newcompounds with a variety of pharmacological activity [2,3]. Basing on pyrroles, anti-tumor agent sunitinib, the anti-hyperlipidemic atorvastatin [2,3], neotropic aloracetam [2],antipsychotic elopiprazole [2], and nonsteroidal anti-inflammatory agent tolmetin [2]were created.

The pyrimidine ring is a main structural moiety of nucleic acids, vitamins, coenzymes,and uric acid [4], as well as the frequent scaffold in medicines [4,5]. According to the liter-ature data, the presence of the amino group in pyrimidine enhances its pharmacologicalproperties [5]. The aminopyrimidine ring is a fragment of nucleotide bases in DNA andRNA, which are important components of living cells [4]. Substituted 2-aminopyrimidinesexhibit cardiotonic [6], antitrypanosomal and antiplasmodial [7], antimicrobial [8–11]and antiplatelet aggregation activity [12]. They are also ligands of histamine H4 and H3receptors [13,14], inhibitors of IRAK4 (interleukin-1 receptor-associated kinase 4) [15],the vascular endothelial growth factor inhibitor [16], serine/threonine protein kinase in-hibitors, candidates for treating drug-resistant tuberculosis [17]. There are numerous2-aminopyrimidine-tailored pharmaceuticals [18,19] including antiviral (Lamivudine [18],Etravirine and Rilpivirine [19]), anti-cancer (Imatinib [18,19], Erlotinib, Lapatinib [18], Nilo-tinib, Dabrafenib, Ceritinib, Osimertinib, and Pazopanib [19]), anxiolytic (Buspirone) [19],hypolipidemic (Rosuvastatin) [18], etc.

2-Aminopyrimidines with pyrrole substituents represent molecular systems, whichcould be particularly promising for medicinal chemistry, due to the presence of two

Molecules 2021, 26, 1692. https://doi.org/10.3390/molecules26061692 https://www.mdpi.com/journal/molecules

Molecules 2021, 26, 1692 2 of 16

pharmacologically active units in their structure. This assumption is supported by the factthat among pyrrole–aminopyrimidines there are inhibitors of JAK2 (Janus kinase 2) [20,21],Cdc7 kinase (Cell division cycle 7-related protein kinase) [22,23], and Polo-like kinase 1 [24],as well as representatives with prominent antifungal activity against Aspergillus niger [25].

The fact that pyrrole–aminopyrimidines have a great potential for cancer treatment [20–24]generates interest in the targeted synthesis of these derivatives.

Few known syntheses of pyrrole–aminopyrimidine ensembles are based on threeapproaches. The first is to build up the pyrrole moiety on aminopyrimidines starting from1-(2-aminopyrimidin-4-yl)-2-bromoethanones [20,23,26].

The second approach involves construction of the aminopyrimidine ring via theaddition of guanidine to pyrroles with ethylenic substituents. Among the latter are 3-dimethylamino-2-(pyrrole-2-carbonyl)acrylonitrile [27], benzylidene acetyl pyrrole [28],pyrrolylenaminone [20], pyrrolyl vinamidinium salts [29].

The third approach to the synthesis of pyrrole–aminopyrimidine ensembles is thecoupling of halopyrimidines with pyrroles under Buchwald–Hartwig conditions [21] ortheir boronate derivative under Suzuki reaction conditions and PdCl2(dppf) catalysis [21].(Pyrrol-2-yl)-2-aminopyrimidine was also obtained from N-Boc-pyrrole, which was depro-tonated upon treatment with LiTMP (Lithium tetramethylpiperidide) and, after subsequenttransmetalation (using ZnCl2·TMEDA) and coupling with 2,4-dichloropyrimidine, wastransformed into N-Boc-2-(2-chloro-4-pyrimidyl)pyrrole [30]. The chloro group of the latterwas substituted with allylamine, and after subsequent cleavage of the allyl group underclassical conditions afforded the target product.

The most common approach to the synthesis of aminopyrimidines, i.e., cycloconden-sation of alkynones with guanidine [31–38], was not always applied to the preparation ofpyrrole–aminopyrimidines.

To our knowledge, there is only one work concerning the synthesis of pyrrole–aminopyrimidines from guanidine and pyrrol-2-ylhexynones [39], obtained by glyoxylationof N-methyl- and N-benzylpyrroles with oxalyl chloride and subsequent Pd/Cu-catalyzeddecarbonylative alkynylation of the pyrrolylglyoxylyl chlorides with hexyne (Scheme 1).

Scheme 1. Synthesis of pyrrole–aminopyrimidines from pyrrol-2-ylhexynones and guanidine. Previ-ous work [39].

This is likely due to the fact that, until recently, alkynones with pyrrole substituentswere difficult to obtain. Such compounds have become readily available owing to thediscovery of the cross-coupling reaction of pyrroles with acylhaloacetylenes in the mediumof solid oxides and metal salts [40–42], and was widely used by us in the synthesis ofdiverse pyrrole heterocyclic ensembles and fused heterocyclic systems [42].

2. Results and Discussion

In the present paper, we have developed an effective method for the assembly ofpyrrole–aminopyrimidines via the reaction of 2-acylethynylpyrroles 1a–v, obtained accord-ing to Scheme 2, with guanidine nitrate.

Molecules 2021, 26, 1692 3 of 16

Scheme 2. Synthesis of 2-acylethynylpyrroles.

To commence the investigation, 2-benzoylethynyl-5-phenylpyrrole (1l, 1.0 equiv) wasrefluxed with guanidine nitrate (2, 1.0 equiv) in the presence of Na2CO3 (2.0 equiv) inMeCN for 4 h (Scheme 3). These conditions are known [36] to be effective for the synthesisof 2-aminopyrimidines from alkynones and guanidine. However, in our case, the yield ofthe target pyrrole–aminopyrimidine 3l did not exceed 11%.

Scheme 3. The reaction of 2-benzoylethynyl-5-phenylpyrrole (1l) with guanidine nitrate.

Therefore, in order to find optimal reaction conditions for the construction of pyrrole–aminopyrimidine ensembles, we screened combinations of bases, solvents, reagent ratio,temperature, and reaction time using the same pyrrole 1l and guanidine nitrate as referencereagents (Scheme 3, Table 1). The reaction was carried out open to air and controlled by the1H-NMR spectroscopy.

The results showed that the yield of the pyrrole–aminopyrimidine 3l depended on thenature of the base, solvent and other reaction conditions. As seen from Table 1, among thebases tested, only KOH, Cs2CO3 and K3PO4 demonstrated a good activity (entries 11, 12,16 and 18–22). However, in the case of the latter two bases, a significant excess of both thebase and guanidine should be used to achieve a preparatively acceptable yield of aminopy-rimidine 3l. As the solvents, MeCN, t-BuOH, THF (tetrahydrofuran) and DMSO (dimethylsulfoxide) were checked and it was established that yields of aminopyrimidine 3l reached amaximum, when the reaction was carried out in DMSO in the presence of KOH (entry 22).Using this catalytic system, the effect of the ratio of reagents and reaction conditions onthe yield of the target product was examined. Finally, the desired aminopyrimidine 3l wasobtained in 89% isolated yield, when 2-benzoylethynyl-5-phenylpyrrole (1l), guanidineand KOH in a ratio of 1:1:1.5 were reacted in DMSO at 110–115 ◦C for 4 h (entry 22).

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Table 1. Effect of reaction conditions on the synthesis of pyrrole–aminopyrimidine ensemble 3l from2-benzoylethynyl-5-phenylpyrrole (1l) and guanidine nitrate 2.

Entry Base Solvent Ratio 1l/2/Base,mol T, ◦C Time, h Content of 3l in the

Reaction Mixture, % a

1 Na2CO3 MeCN 1/1/1.5 82 4 11 b

2 KOH MeCN 1/1/1.5 82 4 68 c

3 Et3N t-BuOH 1/1/1.5 82 4 0

4 DBU t-BuOH 1/1/1.5 82 4 0 d

5 Cs2CO3 THF 1/2/1.5 66 4 06 Cs2CO3 THF 1/2/2 66 14 07 Cs2CO3 THF 1/2/4 66 18 158 Cs2CO3 THF 1/6/12 66 4 629 Cs2CO3 THF 1/10/20 66 4 68

10 Cs2CO3 THF 1/10/20 66 7 7411 Cs2CO3 THF 1/10/20 66 12 8912 Cs2CO3 THF 1/10/20 66 18 9113 K3PO4 DMSO 1/5/6 20 16 014 K3PO4 DMSO 1/5/6 65–70 4 traces15 K3PO4 DMSO 1/5/6 85–90 4 59 e

16 K3PO4 DMSO 1/5/6 85–90 6 80 e

17 KOH DMSO 1/1/2 20 1 018 KOH DMSO 1/2/4 70–75 13 93

19 KOH DMSO 1/1/2 110–115 4 100 (77)

20 KOH DMSO 1/1/1 110–115 4 95 (82)

21 KOH DMSO 1/1.5/2 110–115 4 100 (88)

22 KOH DMSO 1/1/1.5 110–115 4 100 (89)

a The isolated yield of the product is indicated in parentheses; b conversion of pyrrole 1lis 89%; c content of unidentified products is ~20%; d mixture of unidentified compounds;e strong tarring of the reaction mixture. THF: tetrahydrofuran; DMSO: dimethyl sulfoxide.

Having established near to optimal reaction conditions, we have further investigatedthe substrate scope of this reaction (Figure 1). The experiments revealed that the reaction of2-acylethynylpyrroles 1a–v with guanidine nitrate in these conditions proceeded efficientlyand selectively thus offering a short-cut to pyrrole–aminopyrimidine ensembles 3a–v ingood to high yields.

As follows from Figure 1, the reaction tolerates different (aliphatic, cycloaliphatic, aro-matic and vinyl) substituents in the pyrrole ring, i.e., the synthesis has quite general character.

The moderate yield of aminopyrimidine 3a is due to the formation of side products: 3-[2-(2-amino-6-phenylpyrimidin-4-yl)-1H-pyrrol-1-yl]-1-phenyl-3-(1H-pyrrol-2-yl)prop-2-en-1-one (4a, 13%) and 3-[2-amino-4-phenyl-6-(1H-pyrrol-2-yl)pyrimidin-5-yl]-1-phenyl-3-(1H-pyrrol-2-yl)prop-2-en-1-one (5a, 8%) (Scheme 4). Using the reagents ratio of 1a:2:KOH= 1:2:2.5 allowed to increase the yield of the aminopyrimidine 3a to 40%, the content ofadduct 4a in this case in the reaction mixture did not exceed 6% and adduct 5 was notdetected at all.

The formation of pyrrole–aminopyrimidine 3, probably, proceeds as nucleophilic ad-dition of guanidine to the triple bond of 2-acylethynylpyrrole 1, intramolecular cyclizationof adduct A with participation of the carbonyl group and elimination of water from theintermediate 3,4-dihydropyrimidin-4-ol B (Scheme 5).

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Figure 1. Synthesis of pyrrole–aminopyrimidine ensembles 3a–v from 2-acylethynylpyrroles 1a–v and guanidine nitrate.Reagents and conditions: (i) guanidine nitrate (0.40 mmol), KOH·0.5H2O (0.60 mmol), DMSO (8 mL), 110–115 ◦C, 0.5 h;(ii) 2-acylethynylpyrrole (0.40 mmol), 110–115 ◦C, 4 h.

Scheme 4. The reaction of 2-benzoylethynylpyrrole 1a with guanidine nitrate.

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Scheme 5. Proposed route of pyrrole–aminopyrimidine ensembles 3 formation.

The formation of compound 4 likely involves the nucleophilic addition of N-anionC of adduct A, existing in the reaction mixture due to the deprotonating ability of thesuper-base KOH/DMSO system, to the starting 2-acylethynylpyrrole 1a (Scheme 6).

Scheme 6. Proposed route of adduct 4a formation.

Adduct 5, is, probably, a result of the attack of carbocentered anion D of the aminopy-rimidine ring to the triple bond of pyrrole 1a (Scheme 7).

A control experiment showed that adducts 4 and 5 did not result from the directaddition of aminopyrimidine 3a to the triple bond of the starting 2-acylethynylpyrrole 1a.

Scheme 7. Proposed route of adduct 5a formation.

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3. Materials and Methods3.1. General Procedures

1H, 13C, 15N and 19F NMR spectra (Nuclear magnetic resonance spectra) were recordedin CDCl3 and DMSO-d6 using a Bruker Avance 400 NMR spectrometer (Germany, 400.13,100.6, 40.5 and 376.5 MHz, respectively). The assignment of signals in the 1H NMR spectrawas made using COSY and NOESY experiments. Resonance signals of carbon atoms wereassigned based on 1H-13C HSQC and 1H-13C HMBC experiments. The values of the δ 15Nwere measured through the 2D 1H-15N HMBC experiment. The chemical shifts (δ) are givenin ppm and referenced to residual solvent: 7.27 ppm (CDCl3) and 2.50 ppm (DMSO-d6)for 1H, 77.1 ppm (CDCl3) and 39.5 ppm (DMSO-d6) for 13C and 15N-MeNO2 (0.0 ppm),respectively. The 19F chemical shifts were referenced to CFCl3. Coupling constants in hertz(Hz) were measured from one-dimensional spectra and multiplicities were abbreviatedas following: br (broad), s (singlet), d (doublet), dd (doublet of doublets), m (multiplet).The chemical shifts were recorded in ppm, coupling constants (J) in Hz. 1H-,13C- and 19F-NMR spectra of all new synthetized molecules available in Supplementary Materials.

Infrared (IR) spectra were obtained on a Varian 3100 IF-IR spectrometer (Germany;400–4000 cm−1, KBr pellets or films). The (C, H, N) microanalyses were performed on aFlash EA 1112 CHNS-O/MAS (CHN Analyzer, Thermo Fisher Scientific, Monza, Italy)instrument. The chlorine and sulfur content was determined by using the titrimetricmethod. Fluorine content was determined on a SPECOL 11 (Carl Zeiss, Jena, Germany)spectrophotometer. Melting points (uncorrected) were determined with melting pointSMP50 (Stone, Staffordshire, UK).

3.2. Synthetic Procedures

2-Acylethynylpyrroles 1a,f–l,n–r were obtained from pyrroles and 2-acylbromoacetyl-enes accordingly to methodology [40–42]. Physico-chemical characteristics 2-acylethynylpy-rroles 1a,f–l,n–r were given in [40,43–47]. 2-Acylethynylpyrroles 1b,c–e,m,s–v were ob-tained accordingly to the following procedure:

The corresponding pyrrole (1 mmol) and acyl(bromo)acetylene (1 mmol) were care-fully ground in a porcelain mortar with alumina [10-fold amount by weight of combinedmass of pyrrole and acyl(bromo)acetylene] at 20–25 ◦C for 5 min. The reaction mixturewas left for 2 h. Then the mixture was subjected to column chromatography (alumina,eluent–n-hexane/diethyl ether, gradient 1:0–1:1); this afforded pure 2-acylethynylpyrroles1b,c–e,m,s–v.

3-(1-Methyl-1H-pyrrol-2-yl)-1-phenylprop-2-yn-1-one (1b): 182 mg (87%), yellow crystals, m.p.59 ◦C; 1H-NMR (400.13 MHz, CDCl3) δ: 8.20–8.18 (m, 2H, H-2,6, COPh), 7.64–7.61 (m, 1H,H-4, COPh), 7.54–7.50 (m, 2H, H-3,5, COPh), 6.86–6.85 (m, 2H, H-3,5, pyrrole), 6.21–6.20(m, 1H, H-4, pyrrole), 3.85 (s, 3H, NMe); 13C-NMR (100.6 MHz, CDCl3) δ: 176.9, 136.7,133.4, 128.8 (2C), 128.3 (2C), 127.6, 120.9, 112.5, 109.4, 94.7, 87.4, 34.6; IR (KBr) ν: 3114, 2936,2362, 2168, 1630, 1448, 1326, 1255, 1173, 1035, 998, 729, 695, 649. Anal. Calcd. for C14H11NO:C, 80.36%; H, 5.30%; N, 6.69%. Found: C, 80.12%; H, 5.03%; N, 6.37%.

3-(1-Benzyl-1H-pyrrol-2-yl)-1-phenylprop-2-yn-1-one (1c): 271 mg (95%), light yellow crystals,m.p. 111 ◦C; 1H-NMR (400.13 MHz, CDCl3) δ: 8.07–8.04 (m, 2H, H-2,6, COPh), 7.61–7.57(m, 1H, H-4, COPh), 7.47–7.43 (m, 2H, H-3,5, COPh), 7.39–7.35 (m, 2H, H-3,5 Ph), 7.33–7.27(m, 1H, H-4, Ph), 7.23–7.21 (m, 2H, H-2,6, Ph), 6.92–6.91 (m, 2H, H-3,5, pyrrole), 6.28–6.27(m, 1H, H-4, pyrrole), 5.34 (s, 2H, CH2); 13C-NMR (100.6 MHz, CDCl3) δ: 177.4, 137.1, 133.7,129.2 (2C), 129.0 (2C), 128.9, 128.6 (2C), 128.0, 127.2 (2C), 126.9, 121.4, 112.9, 110.3, 95.1, 87.3,51.9; IR (KBr) ν: 3115, 3061, 3027, 2170, 1612, 1572, 1470, 1445, 1412, 1329, 1308, 1260, 1218,1165, 1072, 1000, 748, 730, 697, 651. Anal. Calcd. for C20H15NO: C, 84.19%; H, 5.30%; N,4.91%. Found: C, 84.12%; H, 5.37%; N, 4.87%.

3-(4-Ethyl-5-propyl-1H-pyrrol-2-yl)-1-phenylprop-2-yn-1-one (1d): 125 mg (47%), yellow crys-tals, m.p. 162 ◦C; 1H-NMR (400.13 MHz, CDCl3) δ: 8.57 (br s, 1H, NH), 8.19–8.16 (m, 2H,H-2,6, Ph), 7.61–7.58 (m, 1H, H-4, Ph), 7.51–7.47 (m, 2H, H-3,5, Ph), 6.74 (d, J = 2.3 Hz,

Molecules 2021, 26, 1692 8 of 16

1H, H-3, pyrrole), 2.61–2.57 (m, 2H, CH2), 2.47–2.41 (m, 2H, CH2), 1.69–1.60 (m, 2H, CH2),1.21–1.17 (m, 3H, CH3), 0.99–0.96 (m, 3H, CH3); 13C-NMR (100.6 MHz, CDCl3) δ: 177.7,137.2, 136.2, 133.6, 129.3 (2C), 128.5 (2C), 124.8, 121.2, 107.1, 93.7, 91.5, 28.1, 22.8, 18.8, 15.3,13.9; IR (KBr) ν: 3438, 2955, 2867, 2430, 2362, 2160, 1601, 1564, 1473, 1345, 1256, 1164, 1033,829, 692, 645. Anal. Calcd. for C18H19NO: C, 81.47%; H, 7.22%; N, 5.28%. Found: C, 81.23%;H, 7.08%; N, 5.19%.

3-(5-Butyl-4-propyl-1H-pyrrol-2-yl)-1-phenylprop-2-yn-1-one (1e): 150 mg (51%), yellow crys-tals, m.p. 62–63 ◦C; 1H-NMR (400.13 MHz, CDCl3) δ: 8.57 (br s, 1H, NH), 8.19–8.17 (m, 2H,H-2,6, Ph), 7.61–7.58 (m, 1H, H-4, Ph), 7.51–7.48 (m, 2H, H-3,5, Ph), 6.71 (d, J = 2.3 Hz, 1H,H-3, pyrrole), 2.62–2.59 (m, 2H, CH2), 2.40–2.36 (m, 2H, CH2), 1.61–1.55 (m, 4H, 2CH2),1.41–1.33 (m, 2H, CH2), 0.98–0.93 (m, 6H, 2CH3); 13C-NMR (100.6 MHz, CDCl3) δ: 177.7,137.1, 137.0, 133.4, 129.2 (2C), 128.4 (2C), 122.9, 121.9, 106.9, 93.9, 92.4, 31.6, 27.6, 25.8, 24.0,22.4, 13.9, 13.7; IR (film) ν: 3298, 2956, 2928, 2865, 2377, 2157, 1614, 1567, 1469, 1318, 1241,1164, 1040, 976, 823, 698, 646. Anal. Calcd. for C20H23NO: C, 81.87%; H, 7.90%; N, 4.77%.Found: C, 81.64%; H, 7.55%; N, 4.70%.

1-(Furan-2-yl)-3-(5-phenyl-1H-pyrrol-2-yl)prop-2-yn-1-one (1m): 154 mg (59%), red crystals,m.p. 164 ◦C; 1H-NMR (400.13 MHz, CDCl3) δ: 9.15 (br s, 1H, NH), 7.69–7.68 (m, 1H, H-5,furyl), 7.57–7.55 (m, 2H, H-2,6, Ph), 7.45–7.39 (m, 3H, H-3,4,5, Ph), 7.34–7.30 (m, 1H, H-3,furyl), 6.91 (dd, J = 2.5, 3.8 Hz, 1H, H-3, pyrrole), 6.60–6.57 (m, 2H, H-4, furyl, H-4, pyrrole);13C-NMR (100.6 MHz, CDCl3) δ: 164.7, 153.2, 147.7, 137.7, 131.0, 129.2 (2C), 128.1, 124.8(2C), 122.6, 120.1, 112.7, 110.7, 108.4, 92.5, 88.1; IR (KBr) ν: 3311, 2172, 1661, 1608, 1550, 1457,1388, 1258, 1160, 1043, 972, 910, 760, 695, 593. Anal. Calcd. for C17H11NO2: C, 78.15%; H,4.24%; N, 5.36%. Found: C, 78.04%; H, 4.13%; N, 5.22%.

3-(4,5-Diphenyl-1-vinyl-1H-pyrrol-2-yl)-1-phenylprop-2-yn-1-one (1s): 291 mg (78%), yellowcrystals, m.p. 106 ◦C; 1H-NMR (400.13 MHz, CDCl3) δ: 8.21–8.20 (m, 2H, Ph), 7.65–7.62(m, 1H, Ph), 7.55–7.51 (m, 2H, Ph), 7.42–7.40 (m, 3H, Ph), 7.33–7.31 (m, 2H, Ph), 7.23–7.15(m, 6H, Ph, H-3, pyrrole), 6.79 (dd, J = 9.0, 15.8 Hz, 1H, HX), 5.19 (d, J = 15.8 Hz, 1H, HB),5.67 (d, J = 9.0 Hz, 1H, HA); 13C-NMR (100.6 MHz, CDCl3) δ: 177.4, 137.1, 135.3, 134.2,133.8, 131.0 (2C), 130.9, 130.6, 129.4 (2C), 128.8, 128.7 (2C), 128.6 (2C), 128.4 (2C), 128.1 (2C),126.5, 125.2, 123.1, 111.9, 108.8, 95.4, 87.8; IR (KBr) ν: 3060, 2162, 1617, 1575, 1455, 1385,1310, 1269, 1165, 1008, 821, 767, 697. Anal. Calcd. for C27H19NO: C, 86.84%; H, 5.13%; N,3.75%. Found: C, 86.61%; H, 5.03%; N, 3.88%.

3-(5-(4-Chlorophenyl)-1-vinyl-1H-pyrrol-2-yl)-1-phenylprop-2-yn-1-one (1t): 289 mg (87%), yel-low crystals, m.p. 100–102 ◦C; 1H-NMR (400.13 MHz, CDCl3) δ: 8.19–8.17 (m, 2H, H-2,6,COPh), 7.64–7.61 (m, 1H, H-4, COPh), 7.54–7.50 (m, 2H, H-3,5, COPh), 7.41–7.40 (m, 4H,H-2,3,5,6, 4-Cl-C6H4), 7.02 (d, J = 3.9 Hz, 1H, H-3, pyrrole), 6.88 (dd, J = 8.8, 15.8 Hz, 1H,HX), 6.36 (d, J = 3.9 Hz, 1H, H-4, pyrrole), 5.69 (d, J = 15.8 Hz, 1H, HB), 5.32 (d, J = 8.8 Hz,1H, HA); 13C-NMR (100.6 MHz, CDCl3) δ: 177.4, 137.8, 137.0, 134.4, 133.9, 130.7, 130.2 (2C),129.9, 129.4 (2C), 128.9 (2C), 128.6 (2C), 123.4, 113.6, 111.7, 110.3, 95.4, 87.7; IR (film) ν: 3063,2236, 2172, 1630, 1458, 1313, 1259, 1093, 993, 780, 698. Anal. Calcd. for C21H14NOCl: C,76.02%; H, 4.25%; Cl, 10.68%; N, 4.22%. Found: C, 75.91%; H, 4.11%; Cl, 10.57%; N, 4.37%.

3-(5-(2-Fluorophenyl)-1-vinyl-1H-pyrrol-2-yl)-1-(furan-2-yl)prop-2-yn-1-one (1u): 226 mg (74%),yellow crystals, m.p. 55–57 ◦C; 1H-NMR (400.13 MHz, CDCl3) δ: 7.68–7.67 (m, 1H, H-5,furyl), 7.44–7.35 (m, 3H, H-4,5,6, 2-F-C6H4), 7.25–7.15 (m, 2H, H-3, 2-F-C6H4, H-3, furyl),7.01 (d, J = 3.8 Hz, 1H, H-3, pyrrole), 6.89 (dd, J = 8.9, 15.8 Hz, 1H, HX), 6.60 (dd, J = 1.8,3.7 Hz, 1H, H-4, furyl), 6.37 (d, J = 3.8 Hz, 1H, H-4, pyrrole), 5.57 (d, J = 15.8 Hz, 1H, HB),5.14 (d, J = 8.9 Hz, 1H, HA); 13C-NMR (100.6 MHz, CDCl3) δ: 164.1, 159.3 (d, 1JCF = 249.2Hz, C-2, 2-F-C6H4), 152.8, 147.5, 132.5, 131.5, 130.5 (d, 3JCF = 8.3 Hz, C-4, 2-F-C6H4), 130.2(d, 4JCF = 2.4 Hz, C-5, 2-F-C6H4), 124.1 (d, 3JCF = 3.7 Hz, C-6, 2-F-C6H4), 123.0, 119.8, 119.1(d, 2JCF = 14.9 Hz, C-1, 2-F-C6H4), 115.9 (d, 2JCF = 21.6 Hz, C-3, 2-F-C6H4), 112.8, 112.5 (2C),108.0, 94.1, 86.3; 19F-NMR (376.5 MHz, CDCl3) δ: −112.8. IR (KBr) ν: 2925, 2361, 2175, 1626,

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1458, 1394, 1280, 1037, 759. Anal. Calcd. for C19H12FNO2: C, 74.75%; H, 3.96%; F, 6.22%; N,4.59%. Found: C, 74.68%; H, 3.77%; F, 6.18%; N, 4.63%.

3-(5-(2-Fluorophenyl)-1-vinyl-1H-pyrrol-2-yl)-1-(thiophen-2-yl)prop-2-yn-1-one (1v): 260 mg(81%), yellow crystals, m.p. 67–69 ◦C; 1H-NMR (400.13 MHz, CDCl3) δ: 7.94 (dd, J = 1.0,3.8 Hz, 1H, H-3, thienyl), 7.72 (dd, J = 1.0, 4.9 Hz, 1H, H-5, thienyl), 7.44–7.38 (m, 2H, H-4,6,2-F-C6H4), 7.25–7.15 (m, 3H, H-3,5, 2-F-C6H4, H-4, thienyl), 7.02 (d, J = 3.8 Hz, 1H, H-3,pyrrole), 6.90 (dd, J = 8.8, 15.8 Hz, 1H, HX), 6.39 (d, J = 3.8 Hz, 1H, H-4, pyrrole), 5.53(d, J = 15.8 Hz, 1H, HB), 5.16 (d, J = 8.8 Hz, 1H, HA); 13C-NMR (100.6 MHz, CDCl3) δ: 168.9,159.4 (d, 1JCF = 249.2 Hz, C-2, 2-F-C6H4), 144.7, 134.6, 134.2, 132.4, 131.5 (d, 4JCF = 2.9 Hz,C-5, 2-F-C6H4), 130.5 (d, 3JCF= 7.9 Hz, C-4, 2-F-C6H4), 130.3, 128.2, 124.2 (d, 3JCF = 3.7 Hz,C-6, 2-F-C6H4), 123.0, 119.2 (d, 2JCF = 14.5 Hz, C-1, 2-F-C6H4), 115.9 (d, 2JCF = 22.0 Hz, C-3,2-F-C6H4), 112.9, 112.7, 108.5, 94.2, 85.9; 19F-NMR (376.5 MHz, CDCl3) δ: −112.6. IR (KBr)ν: 2925, 2859, 2361, 2170, 1603, 1462, 1409, 1267, 1226, 1045, 966, 760, 716. Anal. Calcd.for C19H12FNOS: C, 71.01%; H, 3.76%; F, 5.91%; N, 4.36%; S, 9.98%. Found: C, 70.88%; H,3.66%; F, 5.70%; N, 4.45%; S, 9.61%.

General Procedure for the pyrrole–aminopyrimidine ensembles 3a–v synthesis: A mixture ofguanidine nitrate (49 mg, 0.40 mmol) and KOH·0.5H2O (39 mg, 0.60 mmol) was stirredin DMSO (8 mL) at 110–115 ◦C for 30 min. Then the 2-acylethynylpyrrole 1 (0.40 mmol)was added, and the mixture was stirred for 4 h. After cooling to 20–25 ◦C, the reactionmixture was diluted with saturated solution of NaCl (40 mL). The precipitate was filteredoff, washed with water (3 × 20 mL) and dried. The obtained pyrrole–aminopyrimidineswere purified by column chromatography (SiO2, eluent–n-hexane/diethyl ether, gradient1:0–0:1).

4-Phenyl-6-(1H-pyrrol-2-yl)pyrimidin-2-amine (3a): 24 mg (25%), beige crystals, m.p. 96 ◦C;1H-NMR (400.13 MHz, CDCl3) δ: 9.75 (br s, 1H, NH), 8.04–8.02 (m, 2H, H-2,6, Ph), 7.50–7.49 (m, 3H, H-3,4,5, Ph), 7.28 (s, 1H, H-5, pyrimidine), 6.95–6.92 (m, 2H, H-3,5, pyrrole),6.35–6.34 (m, 1H, H-4, pyrrole), 5.13 (br s, 2H, NH2); 13C-NMR (100.6 MHz, CDCl3) δ: 165.5(C-6, pyrimidine), 163.3 (C-2, pyrimidine), 158.3 (C-4, pyrimidine), 137.8 (C-1, Ph), 130.4(C-4, Ph), 129.9 (C-2, pyrrole), 128.8 (C-3,5, Ph), 127.1 (C-2,6, Ph), 121.5 (C-5, pyrrole), 110.8(C-4, pyrrole), 110.5 (C-3, pyrrole), 101.9 (C-5, pyrimidine); 15N-NMR (40.5 MHz, CDCl3)δ: −304.9 (NH2), −233.8 (NH), −157.3 (N-1), −148.9 (N-3); IR (KBr) ν: 3464, 3418, 3350,3175, 1634, 1582, 1555, 1534, 1468, 1454, 1423, 1359, 1257, 1227, 1112, 1035, 997, 911, 880, 773,732, 701. Anal. Calcd. for C14H12N4: C, 71.17%; H, 5.12%; N, 23.71%. Found: C, 70.83%; H,4.74%; N, 23.45%.

4-(1-Methyl-1H-pyrrol-2-yl)-6-phenylpyrimidin-2-amine (3b): 81 mg (81%), beige crystals, m.p.129 ◦C; 1H-NMR (400.13 MHz, CDCl3) δ: 8.03–8.01 (m, 2H, H-2,6, Ph), 7.49–7.48 (m, 3H,H-3,4,5, Ph), 7.29 (s, 1H, H-5, pyrimidine), 6.85–6.84 (m, 1H, H-5, pyrrole), 6.79–6.78 (m,1H, H-3, pyrrole), 6.21–6.20 (m, 1H, H-4, pyrrole), 5.07 (br s, 2H, NH2), 4.08 (s, 3H, NMe);13C-NMR (100.6 MHz, CDCl3) δ: 165.1, 163.0, 160.6, 138.8, 130.4, 130.2, 128.7 (2C), 128.3,127.0 (2C), 113.4, 108.2, 104.4, 37.7; IR (KBr) ν: 3478, 3319, 3199, 3059, 2956, 1628, 1570, 1528,1487, 1455, 1433, 1381, 1345, 1216, 1117, 1090, 1057, 838, 802, 766, 736, 694, 644. Anal. Calcd.for C15H14N4: C, 71.98%; H, 5.64%; N, 22.38%. Found: C, 71.80%; H, 5.48%; N, 22.31%.

4-(1-Benzyl-1H-pyrrol-2-yl)-6-phenylpyrimidin-2-amine (3c): 107 mg (82%), light yellow crys-tals, m.p. 112–114 ◦C; 1H-NMR (400.13 MHz, CDCl3) δ: 7.99–7.97 (m, 2H, H-2,6, Ph),7.47–7.46 (m, 3H, H-3,4,5, Ph), 7.31–7.26 (m, 3H, H-3,5, CH2Ph, H-5, pyrimidine), 7.24–7.20(m, 1H, H-4, CH2Ph), 7.11–7.09 (m, 2H, H-2,6, CH2Ph), 6.92–6.91 (m, 1H, H-5, pyrrole),6.89–6.88 (m, 1H, H-3, pyrrole), 6.29–6.28 (m, 1H, H-4, pyrrole), 5.82 (s, 2H, CH2), 4.97 (br s,2H, NH2); 13C-NMR (100.6 MHz, CDCl3) δ: 165.1, 162.9, 160.4, 139.5, 138.0, 130.2, 130.1,128.7 (2C), 128.6 (2C), 128.0, 127.2, 127.0 (2C), 126.7 (2C), 113.9, 108.9, 104.5, 52.6; IR (KBr)ν: 3493, 3319, 3197, 3113, 3023, 2926, 1625, 1569, 1537, 1479, 1453, 1430, 1407, 1359, 1229,1114, 1087, 1025, 834, 802, 769, 739, 720, 694, 643. Anal. Calcd. for C21H18N4: C, 77.28%; H,5.56%; N, 17.17%. Found: C, 77.20%; H, 5.49%; N, 17.23%.

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4-(4-Ethyl-5-propyl-1H-pyrrol-2-yl)-6-phenylpyrimidin-2-amine (3d): 103 mg (84%), yellowcrystals, m.p. 162 ◦C; 1H-NMR (400.13 MHz, CDCl3) δ: 9.19 (br s, 1H, NH), 8.02–8.01(m, 2H, H-2,6, Ph), 7.48–7.47 (m, 3H, H-3,4,5, Ph), 7.20 (s, 1H, H-5, pyrimidine), 6.75(d, J = 2.2 Hz, 1H, H-3, pyrrole), 4.95 (br s, 2H, NH2), 2.61–2.57 (m, 2H, CH2), 2.49–2.44(m, 2H, CH2), 1.69–1.64 (m, 2H, CH2), 1.24–1.20 (m, 3H, CH3), 1.00–0.96 (m, 3H, CH3);13C-NMR (100.6 MHz, CDCl3) δ: 165.0, 163.2, 158.1, 138.1, 133.2, 130.1, 128.7 (2C), 127.1,127.0 (2C), 124.6, 110.7, 101.3, 28.0, 23.1, 19.0, 15.6, 13.9; IR (KBr) ν: 3483, 3307, 3184, 2959,2927, 2867, 1631, 1589, 1566, 1536, 1501, 1458, 1420, 1370, 1324, 1237, 1188, 1072, 1006, 920,824, 768, 696, 642. Anal. Calcd. for C19H22N4: C, 74.48%; H, 7.24%; N, 18.29%. Found: C,74.31%; H, 7.11%; N, 17.98%.

4-(5-Butyl-4-propyl-1H-pyrrol-2-yl)-6-phenylpyrimidin-2-amine (3e): 122 mg (91%), yellowcrystals, m.p. 98–99 ◦C; 1H-NMR (400.13 MHz, CDCl3) δ: 9.19 (br s, 1H, NH), 8.03–8.00(m, 2H, H-2,6, Ph), 7.48–7.46 (m, 3H, H-3,4,5, Ph), 7.19 (s, 1H, H-5, pyrimidine), 6.72 (d, J =2.2 Hz, 1H, H-3, pyrrole), 4.98 (br s, 2H, NH2), 2.62–2.58 (m, 2H, CH2), 2.43–2.39 (m, 2H,CH2), 1.67–1.57 (m, 4H, 2CH2), 1.44–1.35 (m, 2H, CH2), 1.00–0.93 (m, 6H, 2CH3); 13C-NMR(100.6 MHz, CDCl3) δ: 164.9, 163.2, 158.1, 138.1, 133.9, 130.1, 128.7 (2C), 127.0, 126.9 (2C),122.8, 111.4, 101.3, 32.0, 28.0, 25.7, 24.3, 22.6, 14.1, 13.9; IR (KBr) ν: 3484, 3450, 3311, 3191,2954, 2926, 2863, 1635, 1588, 1565, 1535, 1500, 1459, 1421, 1370, 1333, 1231, 1188, 1073, 1008,919, 812, 766, 696, 644. Anal. Calcd. for C21H26N4: C, 75.41%; H, 7.84%; N, 16.75%. Found:C, 75.34%; H, 7.63%; N, 16.51%.

4-Phenyl-6-(4,5,6,7-tetrahydro-1H-indol-2-yl)pyrimidin-2-amine (3f): 95 mg (82%), dark orangecrystals, m.p. 100–102 ◦C; 1H-NMR (400.13 MHz, CDCl3) δ: 9.32 (br s, 1H, NH), 8.03–8.01 (m, 2H, H-2,6, Ph), 7.48–7.47 (m, 3H, H-3,4,5, Ph), 7.20 (s, 1H, H-5, pyrimidine), 6.68(d, J = 2.0 Hz, 1H, H-3, pyrrole), 5.03 (br s, 2H, NH2), 2.62–2.55 (m, 4H, CH2-4,7), 1.84–1.79(m, 4H, CH2-5,6); 13C-NMR (100.6 MHz, CDCl3) δ: 165.0, 163.1, 158.3, 138.0, 132.2, 130.2,128.7 (2C), 127.8, 127.0 (2C), 120.2, 110.0, 101.4, 23.7, 23.1, 22.9, 22.8; IR (KBr) ν: 3404, 3311,3195, 3060, 2925, 2848, 1593, 1568, 1535, 1503, 1423, 1346, 1224, 1143, 1005, 830, 808, 770, 695.Anal. Calcd. for C18H18N4: C, 74.46%; H, 6.25%; N, 19.30%. Found: C, 74.14%; H, 6.05%;N, 19.18%.

4-(1-Methyl-4,5,6,7-tetrahydro-1H-indol-2-yl)-6-phenylpyrimidin-2-amine (3g): 99 mg (81%),dark yellow crystals, m.p. 182 ◦C; 1H-NMR (400.13 MHz, CDCl3) δ: 8.01–7.99 (m, 2H, H-2,6,Ph), 7.48–7.47 (m, 3H, H-3,4,5, Ph), 7.23 (s, 1H, H-5, pyrimidine), 6.64 (s, 1H, H-3, pyrrole),5.04 (br s, 2H, NH2), 3.91 (s, 3H, NMe), 2.63–2.60 (m, 2H, CH2-7), 2.57–2.54 (m, 2H, CH2-4),1.91–1.86 (m, 2H, CH2-6), 1.79–1.75 (m, 2H, CH2-5); 13C-NMR (100.6 MHz, DMSO-d6) δ:163.1, 162.9, 160.3, 137.7, 134.3, 129.9, 128.4 (2C), 128.1, 126.6 (2C), 117.2, 112.0, 101.5, 32.6,23.1, 22.7, 22.6, 21.7; IR (KBr) ν: 3489, 3376, 2941, 2915, 2363, 1604, 1585, 1561, 1530, 1495,1449, 1401, 1369, 1223, 1183, 1147, 826, 803, 772, 695. Anal. Calcd. for C19H20N4: C, 74.97%;H, 6.62%; N, 18.41%. Found: C, 74.58%; H, 6.41%; N, 18.32%.

4-(2-Furyl)-6-(1-methyl-4,5,6,7-tetrahydro-1H-indol-2-yl)pyrimidin-2-amine (3h): 64 mg (54%),light brown crystals, m.p. 218 ◦C; 1H-NMR (400.13 MHz, CDCl3) δ: 7.56–7.55 (m, 1H, H-5,furyl), 7.17 (s, 1H, H-5, pyrimidine), 7.10–7.09 (m, 1H, H-3, furyl), 6.65 (s, 1H, H-3, pyrrole),6.54 (dd, J = 1.3, 2.0 Hz, 1H, H-4, furyl), 4.99 (br s, 2H, NH2), 3.90 (s, 3H, NMe), 2.61–2.58 (m,2H, CH2-7), 2.56–2.53 (m, 2H, CH2-4), 1.90–1.84 (m, 2H, CH2-6), 1.78–1.74 (m, 2H, CH2-5);13C-NMR (100.6 MHz, CDCl3) δ: 162.7, 160.7, 155.4, 152.6, 144.1, 135.4, 128.7, 118.6, 112.3,112.1, 110.7, 102.0, 33.0, 23.5, 23.2, 23.0, 22.5; IR (KBr) ν: 3474, 3298, 3182, 2931, 2839, 1606,1544, 1533, 1489, 1449, 1398, 1369, 1223, 1183, 1146, 1010, 953, 800, 753, 743. Anal. Calcd. forC17H18N4O: C, 69.37%; H, 6.16%; N, 19.03%. Found: C, 69.14%; H, 6.05%; N, 19.04%.

4-(1-Benzyl-4,5,6,7-tetrahydro-1H-indol-2-yl)-6-phenylpyrimidin-2-amine (3i): 73 mg (48%),yellow crystals, m.p. 128–129 ◦C; 1H-NMR (400.13 MHz, CDCl3) δ: 8.00–7.98 (m, 2H, H-2,6,Ph), 7.49–7.48 (m, 3H, H-3,4,5, Ph), 7.33–7.22 (m, 4H, H-5, pyrimidine, H-3,4,5, CH2Ph),7.06–7.04 (m, 2H, H-2,6, CH2Ph), 6.79 (s, 1H, H-3, pyrrole), 5.82 (s, 2H, CH2Ph), 4.90 (br s,2H, NH2), 2.63–2.61 (m, 2H, CH2-7), 2.53–2.51 (m, 2H, CH2-4), 1.85–1.78 (m, 4H, CH2-5,6);

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13C-NMR (100.6 MHz, CDCl3) δ: 164.6, 162.8, 160.5, 139.7, 138.2, 135.5, 130.0, 128.8, 128.7(2C), 128.5 (2C), 127.0 (2C), 126.7, 126.2 (2C), 119.1, 112.7, 104.1, 48.6, 23.5, 23.2, 23.1, 22.4;IR (KBr) ν: 3426, 3299, 3188, 3031, 2926, 2847, 2361, 1965, 1622, 1560, 1497, 1442, 1409, 1340,1232, 1177, 1104, 830, 768, 699. Anal. Calcd. for C25H24N4: C, 78.92%; H, 6.36%; N, 14.73%.Found: C, 78.83%; H, 6.30%; N, 14.80%.

4-(1-Benzyl-4,5,6,7-tetrahydro-1H-indol-2-yl)-6-(2-furyl)pyrimidin-2-amine (3j): 87 mg (59%),dark yellow crystals, m.p. 182 ◦C; 1H-NMR (400.13 MHz, CDCl3) δ: 7.54–7.53 (m, 1H, H-5,furyl), 7.28–7.25 (m, 2H, H-2,6, Ph), 7.21–7.18 (m, 2H, H-5, pyrimidine, H-4, Ph), 7.06–7.05(m, 1H, H-3, furyl), 7.01–6.99 (m, 2H, H-3,5, Ph), 6.75 (s, 1H, H-3, pyrrole), 6.52 (dd, J = 1.8,3.2 Hz, 1H, H-4, furyl), 5.78 (s, 2H, CH2Ph), 4.80 (br s, 2H, NH2), 2.59–2.56 (m, 2H, CH2-7),2.50–2.47 (m, 2H, CH2-4), 1.82–1.72 (m, 4H, CH2-5,6); 13C-NMR (100.6 MHz, CDCl3) δ:162.6, 160.5, 155.4, 152.6, 144.1, 139.6, 135.7, 128.5 (2C), 128.4, 126.7, 126.2 (2C), 119.1, 113.0,112.1, 110.6, 101.8, 48.5, 23.5, 23.1, 23.0, 22.4; IR (KBr) ν: 3315, 3178, 2997, 2935, 2843, 1643,1603, 1549, 1495, 1458, 1406, 1377, 1242, 1180, 1146, 1103, 1019, 951, 810, 764, 734, 694. Anal.Calcd. for C23H22N4O: C, 74.57%; H, 5.99%; N, 15.12%. Found: C, 74.28%; H, 5.78%; N,15.04%.

4-Phenyl-6-(1-vinyl-4,5,6,7-tetrahydro-1H-indol-2-yl)pyrimidin-2-amine (3k): 82 mg (65%), yel-low crystals, m.p. 118 ◦C; 1H-NMR (400.13 MHz, CDCl3) δ: 8.01–7.99 (m, 2H, H-2,6 Ph),7.51–7.44 (m, 4H, H-3,4,5, Ph, HX), 7.23 (s, 1H, H-5, pyrimidine), 6.68 (s, 1H, H-3, pyrrole),5.10 (br s, 2H, NH2), 5.04 (d, J = 16.0 Hz, 1H, HB), 5.01 (d, J = 8.9Hz, 1H, HA), 2.75–2.72(m, 2H, CH2-7), 2.59–2.56 (m, 2H, CH2-4), 1.86–1.76 (m, 4H, CH2-6, CH2-5); 13C-NMR(100.6 MHz, CDCl3) δ: 165.0, 163.0, 160.2, 138.1, 134.1, 133.1, 130.2, 129.8, 128.8 (2C), 127.0(2C), 120.4, 113.7, 105.4, 105.0, 24.8, 23.6, 23.2, 23.1; IR (KBr) ν: 3485, 3312, 3199, 2927, 2847,1636, 1564, 1537, 1501, 1459, 1397, 1368, 1227, 1184, 1145, 980, 861, 827, 766, 698, 642. Anal.Calcd. for C20H20N4: C, 75.92%; H, 6.37%; N, 17.71%. Found: C, 75.87%; H, 6.33%; N,17.81%.

4-Phenyl-6-(5-phenyl-1H-pyrrol-2-yl)pyrimidin-2-amine (3l): 111 mg (89%), brown crystals,m.p. 194–196 ◦C; 1H-NMR (400.13 MHz, DMSO-d6) δ: 11.55 (br s, 1H, NH), 8.17–8.15(m, 2H, Ph), 7.88–7.85 (m, 2H, Ph), 7.68 (s, 1H, H-5, pyrimidine), 7.53–7.52 (m, 4H, Ph),7.28–7.24 (m, 2H, Ph), 7.06–7.05 (m, 1H, H-3, pyrrole), 6.66–6.65 (m, 1H, H-4, pyrrole), 6.47(br s, 2H, NH2); 13C-NMR (100.6 MHz, DMSO-d6) δ: 163.9, 163.7, 158.1, 137.5, 134.4, 131.8,130.2, 128.6 (2C), 128.5 (2C), 126.7 (2C), 126.6 (2C), 115.6, 115.4, 112.5, 108.2, 99.9; IR (KBr) ν:3442, 3369, 3274, 3161, 3058, 1602, 1570, 1537, 1457, 1432, 1366, 1301, 1235, 1071, 1046, 1002,912, 836, 755, 691, 614. Anal. Calcd. for C20H16N4: C, 76.90%; H, 5.16%; N, 17.94%. Found:C, 76.75%; H, 5.04%; N, 17.88%.

4-(2-Furyl)-6-(5-phenyl-1H-pyrrol-2-yl)pyrimidin-2-amine (3m): 93 mg (77%), brown crystals,m.p. 208–210 ◦C; 1H-NMR (400.13 MHz, DMSO-d6) δ: 11.59 (br s, 1H, NH), 7.92–7.91(m, 1H, H-5, furyl), 7.85–7.83 (m, 2H, H-2,6, Ph), 7.50 (s, 1H, H-5, pyrimidine), 7.43–7.39(m, 2H, H-3,5, Ph), 7.27–7.23 (m, 1H, H-4, Ph), 7.16–7.15 (m, 1H, H-3, furyl), 7.01–7.00(m, 1H, H-4, furyl), 6.71–6.69 (m, 2H, H-3,4, pyrrole), 6.50 (br s, 2H, NH2); 13C-NMR(100.6 MHz, DMSO-d6) δ: 163.5, 158.1, 155.7, 152.5, 145.0, 135.5, 131.9, 131.7 128.7 (2C),126.7, 124.7 (2C), 112.6, 112.5, 110.9, 108.3, 98.1; IR (KBr) ν: 3482, 3454, 3298, 3181, 2924,1631, 1588, 1566, 1541, 1445, 1386, 1351, 1299, 1237, 1214, 1160, 1044, 1011, 879, 812, 750,681, 595, 554, 424. Anal. Calcd. for C18H14N4O: C, 71.51%; H, 4.67%; N, 18.53%. Found: C,71.39%; H, 4.59%; N, 18.65%.

4-[5-(4-Fluorophenyl)-1H-pyrrol-2-yl]-6-phenylpyrimidin-2-amine (3n): 116 mg (88%), lightyellow crystals, m.p. 221–222 ◦C; 1H-NMR (400.13 MHz, CDCl3) δ: 9.75 (br s, 1H, NH),8.05–8.03 (m, 2H, H-2,6, Ph), 7.59–7.56 (m, 2H, H-2,6, 4-F-C6H4), 7.51–7.49 (m, 3H, H-3,4,5,Ph), 7.29 (s, 1H, H-5, pyrimidine), 7.14–7.09 (m, 2H, H-3,5, 4-F-C6H4), 6.96 (dd, J = 0.8,2.6 Hz, 1H, H-3, pyrrole), 6.57 (dd, J = 0.8, 2.9 Hz, 1H, H-4, pyrrole), 5.07 (br s, 2H, NH2);13C NMR (100.6 MHz, DMSO-d6) δ: 163.5 (C-2, pyrimidine), 163.3 (C-6, pyrimidine), 160.7(d, 1JCF = 243.9 Hz, C-4, 4-F-C6H4), 157.7 (C-4, pyrimidine), 137.1 (C-1, Ph), 134.0 (C-5,

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pyrrole), 131.5 (C-2, pyrrole), 129.8 (C-4, Ph), 128.2 (d, 4JCF = 2.9 Hz, C-1, 4-F-C6H4), 128.1(C-3,5, Ph), 126.3 (C-2,6, Ph), 126.2 (d, 3JCF = 8.7 Hz, C-2,6, 4-F-C6H4), 115.1 (d, 2JCF =21.5 Hz, C-3,5, 4-F-C6H4), 112.0 (C-3, pyrrole), 107.8 (C-4, pyrrole), 99.5 (C-5, pyrimidine);15N-NMR (40.5 MHz, DMSO-d6) δ: −298.9 (NH2), −233.8 (NH, pyrrole), −151.2 (N-3),−147.4 (N-1); IR (KBr) ν: 3445, 3388, 3270, 3159, 1602, 1575, 1524, 1478, 1451, 1433, 1366,1301, 1233, 1157, 1047, 832, 765, 697. Anal. Calcd. for C20H15FN4: C, 72.71%; H, 4.58%; F,5.75%; N, 16.96%. Found: C, 72.62%; H, 4.48%; F, 5.60%; N, 17.07%.

4-[5-(4-Chlorophenyl)-1H-pyrrol-2-yl]-6-phenylpyrimidin-2-amine (3o): 117 mg (84%), browncrystals, m.p. 226 ◦C; 1H-NMR (400.13 MHz, CDCl3) δ: 9.80 (br s, 1H, NH), 8.05–8.03 (m,2H, H-2,6, Ph), 7.54–7.49 (m, 5H, H-3,4,5, Ph, H-2,6, 4-Cl-C6H4), 7.39–7.37 (m, 2H, H-3,5,4-Cl-C6H4), 7.29 (s, 1H, H-5, pyrimidine), 6.96–6.95 (m, 1H, H-3, pyrrole), 6.62–6.61 (m, 1H,H-4, pyrrole), 5.11 (br s, 2H, NH2); 13C-NMR (100.6 MHz, DMSO-d6) δ: 164.0, 163.7, 158.1,137.5, 134.1, 132.3, 131.0, 130.9, 130.3, 128.7 (2C), 128.6 (2C), 126.8 (2C), 126.3 (2C), 112.6,108.9, 100.1; IR (KBr) ν: 3434, 2925, 2858, 1622, 1583, 1531, 1470, 1432, 1360, 1290, 1231, 1113,1095, 1048, 829, 770, 692; Anal. Calcd. for C20H15ClN4: C, 69.26%; H, 4.36%; Cl, 10.22%; N,16.15%. Found: C, 69.13%; H, 4.28%; Cl, 10.14%; N, 16.09%.

4-[5-(4-Methoxyphenyl)-1H-pyrrol-2-yl]-6-phenylpyrimidin-2-amine (3p): 108 mg (79%), yellowcrystals, m.p. 217 ◦C; 1H-NMR (400.13 MHz, CDCl3) δ: 9.72 (br s, 1H, NH), 8.05–8.02 (m,2H, H-2,6, Ph), 7.56–7.54 (m, 2H, H-2,6, 4-MeO-C6H4), 7.50–7.49 (m, 3H, H-3,4,5, Ph), 7.28(s, 1H, H-5, pyrimidine), 6.97–6.95 (m, 3H, H-3,5, 4-MeO-C6H4, H-3, pyrrole), 6.54 (dd,J = 0.6, 2.9 Hz, 1H, H-4, pyrrole), 5.06 (br s, 2H, NH2), 3.85 (s, 3H, MeO); 13C-NMR (100.6MHz, DMSO-d6) δ: 163.9, 163.8, 158.4, 158.3, 137.7, 135.7, 131.1, 130.4, 128.7 (2C), 126.8 (2C),126.2 (2C), 124.9, 114.3 (2C), 112.8, 107.4, 99.9, 55.3; IR (KBr) ν: 3484, 3430, 3298, 3144, 2953,2928, 1634, 1569, 1530, 1479, 1455, 1433, 1359, 1251, 1178, 1048, 1030, 1005, 833, 774, 706, 645.Anal. Calcd. for C21H18N4O: C, 73.67%; H, 5.30%; N, 16.36%. Found: C, 73.59%; H, 5.24%;N, 16.27%.

4-Phenyl-6-(1-methyl-5-phenyl-1H-pyrrol-2-yl)pyrimidin-2-amine (3q): 91 mg (70%), yellowcrystals, m.p. 60–62 oC; 1H-NMR (400.13 MHz, CDCl3) δ: 8.05–8.03 (m, 2H, H-2,6, Ph),7.49–7.44 (m, 7H, Ph), 7.40–7.36 (m, 1H, H-4, Ph), 7.33 (s, 1H, H-5, pyrimidine), 6.90 (d, J =3.8 Hz, 1H, H-3, pyrrole), 6.32 (d, J = 3.8 Hz, 1H, H-4, pyrrole), 5.11 (br s, 2H, NH2), 3.98 (s,3H, NMe); 13C-NMR (100.6 MHz, CDCl3) δ: 165.2, 163.0, 160.7, 140.8, 138.1, 132.9, 132.6,130.3, 129.3 (2C), 128.8 (2C), 128.6 (2C), 127.6, 127.1 (2C), 113.5, 109.6, 105.1, 35.7; IR (KBr) ν:3476, 3397, 3303, 3182, 3059, 1565, 1528, 1455, 1293, 1347, 1312, 1221, 1113, 1087, 1027, 989,919, 836, 757, 695, 642. Anal. Calcd. for C21H18N4: C, 77.28%; H, 5.56%; N, 17.17%. Found:C, 77.03%; H, 5.32%; N, 17.09%.

4-Phenyl-6-(5-phenyl-1-vinyl-1H-pyrrol-2-yl)pyrimidin-2-amine (3r): 123 mg (91%), light yellowcrystals, m.p. 124–125 ◦C; 1H-NMR (400.13 MHz, CDCl3) δ: 8.03–8.01 (m, 2H, Ph), 7.62 (dd,J = 8.5, 15.8 Hz, 1H, HX), 7.50–7.46 (m, 5H, Ph), 7.42–7.38 (m, 2H, Ph), 7.34–7.31 (m, 1H, Ph),7.30 (s, 1H, H-5, pyrimidine), 6.89 (d, J = 3.7 Hz, 1H, H-3, pyrrole), 6.38 (d, J = 3.7 Hz, 1H,H-4, pyrrole), 5.10 (br s, 2H, NH2), 4.96 (d, J = 8.5 Hz, 1H, HA), 4.68 (d, J = 15.8 Hz, 1H,HB); 13C-NMR (100.6 MHz, CDCl3) δ: 165.3, 163.1, 160.2, 138.9, 137.8, 133.0, 132.8, 132.7,130.3, 129.3 (2C), 128.8 (2C), 128.2 (2C), 127.3, 127.0 (2C), 114.6, 111.8, 111.2, 105.8; IR (KBr)ν: 3463, 3407, 3312, 3187, 3060, 2953, 2922, 2854, 1622, 1566, 1531, 1451, 1429, 1389, 1376,1343, 1291, 1220, 1076, 1026, 963, 900, 837, 761, 695, 640. Anal. Calcd. for C22H18N4: C,78.08%; H, 5.36%; N, 16.56%. Found: C, 78.14%; H, 5.31%; N, 16.32%.

4-(4,5-diphenyl-1-vinyl-1H-pyrrol-2-yl)-6-phenylpyrimidin-2-amine (3s): 146 mg (88%), yellowcrystals, m.p. 202 ◦C; 1H-NMR (400.13 MHz, CDCl3) δ: 8.06–8.03 (m, 2H, H, Ph), 7.51–7.49(m, 3H, Ph, HX), 7.40–7.32 (m, 7H, Ph), 7.21–7.13 (m, 5H, Ph, H-5, pyrimidine), 7.06 (s, 1H,H-3, pyrrole), 5.10 (br s, 2H, NH2), 4.89 (d, J = 8.2 Hz, 1H, HA), 4.60 (d, J = 16.4 Hz, 1H,HB); 13C-NMR (100.6 MHz, CDCl3) δ: 165.4, 163.1, 160.2, 137.8, 135.3, 137.8, 132.4, 132.3,131.8, 131.4 (2C), 130.4, 128.8 (2C), 128.5 (2C), 128.2 (2C), 128.1 (2C), 128.0, 127.1 (2C), 125.9,125.0, 114.9, 110.8, 106.1. IR (KBr) ν: 3418, 3059, 2363, 1637, 1588, 1567, 1535, 1498, 1449,

Molecules 2021, 26, 1692 13 of 16

1408, 1291, 1206, 1075, 955, 910, 832, 770, 696, 638. Anal. Calcd. for C28H22N4: C, 81.13%; H,5.35%; N, 13.52%. Found: C, 78.99%; H, 5.16%; N, 13.37%.

4-[5-(4-Chlorophenyl)-1-vinyl-1H-pyrrol-2-yl]-6-phenylpyrimidin-2-amine (3t): 78 mg (52%),light brown crystals, m.p. 156 ◦C; 1H-NMR (400.13 MHz, CDCl3) δ: 8.04–8.01 (m, 2H, H-2,6,Ph), 7.63 (dd, J = 8.5, 15.8 Hz, 1H, HX), 7.51–7.49 (m, 3H, H-3,4,5, Ph), 7.41–7.35 (m, 4H,4-Cl-C6H4), 7.29 (s, 1H, H-5, pyrimidine), 6.88 (d, J = 3.8 Hz, 1H, H-3, pyrrole), 6.36 (d, J =3.8 Hz, 1H, H-4, pyrrole), 5.16 (br s, 2H, NH2), 5.99 (d, J = 8.5 Hz, 1H, HA), 4.67 (d, J = 15.8Hz, 1H, HB); 13C-NMR (100.6 MHz, CDCl3) δ: 165.5, 163.0, 160.1, 137.8, 137.5, 133.3, 133.2,132.7, 131.5, 130.6 (2C), 130.5, 128.8 (2C), 128.5 (2C), 127.1 (2C), 114.5, 112.2, 111.7, 105.8; IR(KBr) ν: 3499, 3441, 3313, 3189, 2362, 1617, 1565, 1532, 1458, 1434, 1384, 1224, 1083, 1010,957, 896, 831, 766, 700, 642, 580, 521. Anal. Calcd. for C22H17ClN4: C, 70.87%; H, 4.60%; Cl,9.51%; N, 15.03%. Found: C, 70.77%; H, 4.38%; Cl, 9.51%; N, 15.02%.

4-[5-(2-Fluorophenyl)-1-vinyl-1H-pyrrol-2-yl]-6-(2-furyl)pyrimidin-2-amine (3u): 104 mg (75%),orange crystals, m.p. 169 ◦C; 1H-NMR (400.13 MHz, CDCl3) δ: 7.63–7.56 (m, 2H, HX, H-5,furyl), 7.44–7.40 (m, 1H, H-6, 2-F-C6H4), 7.37–7.32 (m, 1H, H-4, 2-F-C6H4), 7.25 (s, 1H, H-5,pyrimidine), 7.21–7.09 (m, 3H, H-3,5, 2-F-C6H4, H-3, furyl), 6.94 (d, J = 3.8 Hz, 1H, H-3,pyrrole), 6.56 (dd, J = 1.8, 3.4 Hz, 1H, H-4, furyl), 6.39 (d, J = 3.8 Hz, 1H, H-4, pyrrole),5.19 (br s, 2H, NH2), 4.87 (d, J = 8.5 Hz, 1H, HA), 4.62 (d, J = 15.8 Hz, 1H, HB); 13C-NMR(100.6 MHz, CDCl3) δ: 162.9, 160.0, 159.4 (d, 1JCF = 248.3 Hz, C-2, 2-F-C6H4), 156.2, 152.3,144,4, 133.2, 132.5 (d, 3JCF = 5.9 Hz, C-4, 2-F-C6H4), 131.9, 131.8, 129.7 (d, 3JCF = 8.1 Hz, C-6,2-F-C6H4), 124.1 (d, 4JCF = 3.4 Hz, C-5, 2-F-C6H4), 121.4 (d, 2JCF = 14.9 Hz, C-1, 2-F-C6H4),115.9 (d, 2JCF = 22.0 Hz, C-3, 2-F-C6H4), 114.3, 112.7, 112.2, 111.3, 109.7, 103.3; IR (KBr) ν:3433, 3363, 3195, 1631, 1600, 1550, 1459, 1408, 1222, 1160, 1108, 1079, 1017, 945, 817, 771, 750.Anal. Calcd. for C20H15FN4O: C, 69.35%; H, 4.37%; F, 5.49%; N, 16.18%. Found: C, 69.27%;H, 4.15%; F, 5.36%; N, 16.11%.

4-[5-(2-Fluorophenyl)-1-vinyl-1H-pyrrol-2-yl]-6-(2-thienyl)pyrimidin-2-amine (3v): 99 mg (68%),brown crystals, m.p. 144 ◦C; 1H-NMR (400.13 MHz, CDCl3) δ: 7.73–7.72 (m, 1H, H-6, 2-F-C6H4), 7.57 (dd, J = 8.5, 15.7 Hz, 1H, Hx), 7.48–7.47 (m, 1H, H-3, thienyl), 7.43–7.40 (m, 1H,H-5, thienyl), 7.38–7.33 (m, 1H, H-4, 2-F-C6H4),7.22 (s, 1H, H-5, pyrimidine), 7.19–7.09 (m,3H, H-3,5, 2-F-C6H4, H-4, thienyl), 6.91 (d, J = 3.7 Hz, 1H, H-3, pyrrole), 6.39 (d, J = 3.7 Hz,1H, H-4, pyrrole), 5.08 (br s, 2H, NH2), 4.89 (d, J = 8.5 Hz, 1H, HA), 4.65 (d, J = 15.7 Hz,1H, HB); 13C-NMR (100.6 MHz, CDCl3) δ: 162.9, 159.9, 159.8, 159.5 (d, 1JCF = 248.4 Hz, C-2,2-F-C6H4), 143.2, 133.2, 132.5 (d, 2JCF = 21.5 Hz, C-1, 2-F-C6H4), 132.0, 131.9, 129.8 (d, 3JCF= 8.0 Hz, C-4, 2-F-C6H4), 129.0, 128.1, 126.7, 124.1 (d, 4JCF = 2.8 Hz, C-5, 2-F-C6H4), 121.4 (d,3JCF = 15.0 Hz, C-6, 2-F-C6H4), 115.9 (d, 2JCF = 22.0 Hz, C-3, 2-F-C6H4), 114.1, 112.7, 109.7,103.8; IR (KBr) ν: 3404, 3340, 3223, 1638, 1567, 1531, 1448, 1431, 1376, 1347, 1223, 1105, 1073,1045, 947, 898, 816, 766, 710. Anal. Calcd. for C20H15FN4S: C, 66.28%; H, 4.17%; F, 5.24%; N,15.46%; S, 8.85%. Found: C, 65.93%; H, 4.02%; F, 5.48%; N, 15.11%; S, 8.79%.

3-[2-(2-Amino-6-phenylpyrimidin-4-yl)-1H-pyrrol-1-yl]-1-phenyl-3-(1H-pyrrol-2-yl)prop-2-en-1-one (4a): 11 mg (13%), yellow crystals, m.p. 137–139 ◦C; 1H-NMR (400.13 MHz, CDCl3)δ: 13.64 (br s, 1H, NH), 7.90–7.85 (m, 4H, H-2,6, COPh, H-2,6, Ph), 7.55–7.51 (m, 1H, H-4,COPh), 7.45–7.42 (m, 5H, H-3,5, COPh, H-3,4,5, Ph), 7.19 (s, 1H, H-5, pyrimidine), 7.16–7.15(m, 2H, H-5, H-5′, pyrrole), 7.06 (dd, J = 1.7, 3.6 Hz, 1H, H-3, pyrrole), 6.76 (s, 1H, HC=), 6.42(dd, J = 2.8, 3.6 Hz, 1H, H-4, pyrrole), 6.28 (dd, J = 2.2, 3.8 Hz, 1H, H-4′, pyrrole), 6.24–6.23(m, 1H, H-3′, pyrrole), 4.88 (br s, 2H, NH2); 13C-NMR (100.6 MHz, CDCl3) δ: 189.9, 165.2,162.9, 158.8, 146.3, 139.4, 137.7, 133.1, 132.8, 130.3, 129.9, 129.3, 128.7 (2C), 128.6 (2C), 128.3(2C), 127.0 (2C), 124.5, 118.6, 114.3, 112.7, 111.9, 109.7, 104.3; 15N-NMR (40.5 MHz, CDCl3)δ: −304.9 (NH2), −220.9 (NH), −208.8 (N-pyrrole), −148.2 (N-1), −145.2 (N-3); IR (KBr)ν: 3480, 3401, 3356, 3120, 3106, 1623, 1577, 1526, 1438, 1353, 1320, 1297, 1220, 1184, 1128,1088, 1036, 998, 931, 909, 881, 833, 768, 696, 641. Anal. Calcd. for C27H21N5O: C, 75.16%; H,4.91%; N, 16.23%. Found: C, 75.04%; H, 4.77%; N, 16.14%.

Molecules 2021, 26, 1692 14 of 16

3-[2-Amino-4-phenyl-6-(1H-pyrrol-2-yl)pyrimidin-5-yl]-1-phenyl-3-(1H-pyrrol-2-yl)prop-2-en-1-one (5a): 7 mg (8%), dark yellow crystals, m.p. 182 ◦C; 1H-NMR (400.13 MHz, CDCl3) δ:9.96 (br s, 1H, NH’), 8.95 (br s, 1H, NH), 7.59–7.56 (m, 2H, H-2,6, COPh), 7.45–7.42 (m, 1H,H-4, COPh), 7.31–7.30 (m, 1H, H-4, Ph), 7.29 (s, 1H, HC=), 7.25–7.23 (m, 2H, H-3,5,COPh),7.21–7.19 (m, 2H, H-2,6, Ph), 7.14–7.10 (m, 2H, H-3,5, Ph), 6.83–6.82 (m, 1H, H-5′, pyrrole),6.78–6.77 (m, 1H, H-5, pyrrole), 6.72–6.71 (m, 1H, H-3, pyrrole), 6.66–6.65 (m, 1H, H-3′,pyrrole), 6.31–6.30 (m, 1H, H-4′, pyrrole), 6.09–6.06 (m, 1H, H-4, pyrrole), 5.12 (br s, 2H,NH2); 13C-NMR (100.6 MHz, DMSO-d6) δ: 187.7 (C=O), 164.9 (C-4, pyrimidine), 161.4 (C-2,pyrimidine), 154.6 (C-6, pyrimidine), 144.4 (C=), 139.6 (C-1, Ph), 139.1 (C-1, COPh), 132.3(C-2′, pyrrole), 132.0 (C-4, COPh), 128.4 (C-2, pyrrole), 128.3 (C-3,5, COPh), 127.8 (C-2,4,6,Ph), 127.5 (C-2,6, COPh), 127.0 (C-3,5, Ph), 123.8 (C-5′, pyrrole), 120.7 (C-5, pyrrole), 114.9(C-3′, pyrrole), 114.8 (C-5, pyrimidine, HC=), 112.5 (C-3, pyrrole), 110.3 (C-4′, pyrrole),109.4 (C-4, pyrrole); 15N-NMR (40.5 MHz, CDCl3) δ: −225.5 (NH’), −223.7 (NH); IR (KBr)ν: 3471, 3426, 3173, 2967, 2863, 1635, 1597, 1536, 1444, 1418, 1227, 1120, 1034, 1020, 910, 738,697. Anal. Calcd. for C27H21N5O: C, 75.16%; H, 4.91%; N, 16.23%. Found: C, 74.98%; H,4.64%; N, 16.14%.

4. Conclusions

In summary, we developed an effective access to novel families of pyrrole–pyrimidineensembles, decorated with alkyl, cycloalkyl, aryl and vinyl groups, attractive objects fordrug design, by using acylethynylpyrroles as the synthetic platform. This method hasseveral synthetic advantages, such as the one-pot procedure, the use of readily availablestarting materials and good to high yields of the target ensembles and therefore can activatethe interest of both synthetic and pharmaceutical communities.

Supplementary Materials: The following are available online, Figures S1–S68: 1H, 13C and 19FNMR spectra.

Author Contributions: Conceptualization, B.A.T. and L.N.S.; methodology, O.V.P., A.B.B.; chem-istry of all compounds, O.V.P., A.B.B. and E.F.S.; formal analysis, I.A.U.; writing—original draftpreparation, B.A.T., L.N.S. and O.V.P.; writing—review and editing, A.B.B., E.F.S., O.V.P. and A.V.I.All authors have read and agreed to the published version of the manuscript.

Funding: This work was supported by the Russian Science Foundation (Project 19-73-10063).

Institutional Review Board Statement: Not applicable.

Informed Consent Statement: Not applicable.

Data Availability Statement: Data set presented in this study is available in this article.

Acknowledgments: Authors acknowledge Baikal Analytical Center SB RAS for collective use ofthe equipment.

Conflicts of Interest: Authors reports no conflict interests.

Sample Availability: Samples of the compounds are available on request from the correspondingauthors.

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